PROJECT SUMMARY/ABSTRACT This proposal (Project 3) continues to focus on understanding the prevalence and pathophysiology of gastric emptying disturbances, particularly the contribution of chronic hyperglycemia (Aim 1), the effects of modulating gastric emptying on glycemic control (Aim 2), and the contribution of small intestinal sensitivity to symptoms in diabetic gastroparesis (Aim 3). Delayed gastric emptying in diabetes mellitus (DM) is attributed to autonomic dysfunctions, hyperglycemia, loss of interstitial cells of Cajal (Project 1) and an enteropathy (Project 2). The Diabetes Control and Complications Trial and the ongoing Epidemiology of Diabetes Interventions and Complications (EDIC) Study, implicated chronic hyperglycemia in the pathogenesis of complications of type 1 DM (T1DM) other than delayed gastric emptying. However, the contribution of chronic hyperglycemia to delayed gastric emptying in DM is unclear. Our preliminary findings suggest that (i) chronic hyperglycemia is a significant risk factor for delayed gastric emptying in T1DM patients in the EDIC study, (ii) delayed gastric emptying is associated with poorer glycemic control, and (iii) diabetic gastroparesis is associated with increased sensitivity during duodenal nutrient infusion and increased epithelial permeability. Our specific aims are to: (i) compare symptoms, the diabetic phenotype, chronic glycemic control, and epigenetic markers between T1DM patients with normal and delayed GE in the EDIC study, (ii) evaluate the effects of stimulating ghrelin receptors on gastric emptying, control of glycemia, and symptoms in patients with poorly-controlled DM, and (iii) investigate the pathophysiology of increased intestinal chemosensitivity, specifically vagal function, the small bowel epithelial barrier, and GLP-1 in DM. A multi-disciplinary collaborative team will apply innovative approaches to address these hypotheses in a highly refined manner. Each study is designed to understand the pathophysiology of symptoms and/or to improve patient care in humans.